N-(heteroaryl)-1h-indole-2-carboxamide derivatives and their use as vanilloid trpv1 receptor ligands

ABSTRACT

The invention concerns compounds of general formula (I), wherein n, X 1 , X 2 , X 3 , X 4 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5  and W are as defined herein.  
                 
 
Said compounds are ligands of the TRPV 1  vanilloid receptor, and are therefore, useful for treating diseases associated with TRPV 1  receptors, such as pain and inflammation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International application No.PCT/FR2006/000,008, filed Jan. 4, 2006, which is incorporated herein byreference in its entirety; which claims the benefit of priority ofFrench Patent Application No. 05/50,068, filed Jan. 7, 2005.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to N-(heteroaryl)-1H-indole-2-carboxamide-basedcompounds, which show in vitro and in vivo antagonist or agonistactivity for receptors of TRPV1 (or VR1) type. A first subject of theinvention relates to compounds corresponding to the general formula (I)below. Another subject of the invention relates to processes forpreparing the compounds of general formula (I). Another subject of theinvention relates to the use of the compounds of general formula (I)especially in medicaments or in pharmaceutical compositions.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to the general formula (I):

in which

n is equal to 0, 1, 2 or 3;

X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ and Z₅ represent, independently of eachother, a hydrogen or halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₁R₂, nitro, NR₁R₂, C₁-C₆-thioalkyl,—S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅ oraryl group, the aryl being optionally substituted with one or moresubstituents chosen from a halogen and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, nitro or cyano group;

R₁ and R₂ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene or arylgroup; or R₁ and R₂ form, together with the nitrogen atom that bearsthem, an azetidine, pyrrolidine, piperidine, azepine, morpholine,thiomorpholine, piperazine or homopiperazine group, this group beingoptionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene or aryl group;

R₃ and R₄ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl or aryl group;

R₅ represents a C₁-C₆-alkyl or aryl group;

W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;

A represents a 5- to 7-membered heterocycle comprising from one to threeheteroatoms chosen from O, S and N;

the carbon atom(s) of A being optionally substituted with one or moregroups chosen from a hydrogen atom and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl,aryl-C₁-C₆-alkylene, oxo or thio group;

the nitrogen atom(s) of A being optionally substituted with R₆ when thenitrogen is adjacent to a carbon atom substituted with an oxo group, orwith R₇ in the other cases;

R₆ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkyleneor aryl group;

R₇ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkylene,C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-(CO)—,C₁-C₆-fluoroalkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, aryl-C(O)—,aryl-C₁-C₆-alkylene-C(O)—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—,C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—,aryl-S(O)₂- or aryl-C₁-C₆-alkylene-S(O)₂— or aryl group; and

W is other than indolyl.

DETAILED DESCRIPTION OF THE INVENTION

In the case of the compounds of general formula (I):

-   -   the sulfur atom(s) of the heterocycle A may be in oxidized form        (S(O) or S(O)₂);    -   the nitrogen atom(s) of the heterocycle A may be in oxidized        form (N-oxide).

Among the compounds of general formula (I) that are subjects of theinvention, a first subgroup of compounds consists of the compounds forwhich n is equal to 0 or 1.

Among the compounds of general formula (I) that are subjects of theinvention, a second subgroup of compounds consists of the compounds forwhich X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ and Z₅ represent, independently ofeach other, a hydrogen or halogen atom, more particularly a fluorine, ora C₁-C₆-alkyl group, more particularly a methyl, or a C₁-C₆-fluoroalkylgroup, more particularly a CF₃, or a C₁-C₆-alkoxy group, moreparticularly a methoxy.

Among the compounds of general formula (I) that are subjects of theinvention, a third subgroup of compounds consists of the compounds forwhich W is chosen from indolinyl, isoindolinyl, benzofuryl,dihydrobenzofuryl, benzothiophenyl, dihydrobenzothiophenyl,benzoxazolyl, dihydrobenzoxazolinyl, isobenzofuryl,dihydroisobenzofuryl, benzimidazolyl, dihydrobenzimidazolyl, indazolyl,benzothiazolyl, isobenzothiazolyl, dihydroisobenzothiazolyl,benzotriazolyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl,isoquinolyl, dihydroisoquinolyl, etrahydroisoquinolyl, benzoxazinyl,dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl,quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl,dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl,dihydrophthalazinyl, tetrahydrophthalazinyl, tetrahydrobenz[b]azepinyl,tetrahydrobenz[c]azepinyl, tetrahydrobenz[d]azepinyl,tetrahydrobenzo[b][1,4]diazepinyl, tetrahydrobenzo[e][1,4]diazepinyl,tetrahydrobenzo[b][1,4]oxazepinyl and tetrahydrobenzo[b][1,4]thiazepinylgroups; the carbon and/or nitrogen atom(s) of the said group W beingoptionally substituted as defined in the general formula (I).

Among the compounds of the third subgroup, a fourth subgroup ofcompounds consists of the compounds for which W is chosen fromisoquinolyl, dihydroquinolyl, tetrahydroquinolyl, benzoxazinyl,dihydrobenzoxazinyl, benzofuryl, indolinyl, benzoxazolyl, indazolyl,benzimidazolyl, benzothiazolyl, benzotriazolyl, quinolyl andquinoxalinyl groups;

the carbon atom(s) of the said group W being optionally substituted withone or more groups chosen from an oxo group, C₁-C₆-alkyl, moreparticularly methyl or ethyl, or aryl, more particularly phenyl, asdefined in the general formula (I) in relation with A; and/or

the nitrogen atom(s) of the said group W being optionally substitutedwith R₆ when the nitrogen is adjacent to a carbon atom substituted withan oxo group, or with R₇ in the other cases, R₆ and R₇ being as definedin the general formula (I) in relation with A,

with R₆ representing a hydrogen atom or a C₁-C₆-alkyl group, moreparticularly a methyl,

with R₇ representing a hydrogen atom or a C₁-C₆-alkyl group, moreparticularly a methyl, or a C₁-C₆-alkyl-S(O)₂—, more particularly amethylsulfonyl.

A fifth subgroup of compounds consists of the compounds of generalformula (I):

in which

n is equal to 0, 1, 2 or 3;

X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ and Z₅ represent, independently of eachother, a hydrogen or halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₁R₂, nitro, NR₁R₂, C₁-C₆-thioalkyl,—S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅ oraryl group, the aryl being optionally substituted with one or moresubstituents chosen from a halogen and a C₁-C₆alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, nitro or cyano group;

R₁ and R₂ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene or arylgroup; or R₁ and R₂ form, together with the nitrogen atom that bearsthem, an azetidine, pyrrolidine, piperidine, azepine, morpholine,thiomorpholine, piperazine or homopiperazine group, this group beingoptionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene or aryl group;

R₃ and R₄ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl or aryl group;

R₅ represents a C₁-C₆-alkyl or aryl group;

W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;

A represents a 5- to 7-membered heterocycle comprising from one to threeheteroatoms chosen from O, S and N;

the carbon atom(s) of A being optionally substituted with one or moregroups chosen from a hydrogen atom and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl,aryl-C₁-C₆-alkylene, oxo or thio group;

the nitrogen atom(s) of A being optionally substituted with R₆ when thenitrogen is adjacent to a carbon atom substituted with an oxo group, orwith R₇ in the other cases;

R₆ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkyleneor aryl group;

R₇ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkylene,C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-(CO)—,C₁-C₆-fluoroalkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, aryl-C(O)—,aryl-C₁-C₆-alkylene-C(O)—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—,C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—,aryl-S(O)₂- or aryl-C₁-C₆-alkylene-S(O)₂— or aryl group; and

W is other than indolyl;

on condition that when Z₁, Z₂, Z₃, Z₄ and Z₅ simultaneously representhydrogen atoms, then n=2 or 3.

Among the compounds of general formula (I) that are subjects of theinvention, a sixth subgroup of compounds consists of compounds for whichW is other than quinolyl, dihydroquinolyl, tetrahydroquinolyl,isoquinolyl, dihydroisoquinolyl or tetrahydroisoquinolyl groups.

Among the compounds of general formula (I) that are subjects of theinvention, a seventh subgroup of compounds consists of all of thecompounds of general formula (I):

in which

n is equal to 0, 1, 2 or 3;

X₁, X₃, X₄, Z₁, Z₃, Z₄ and Z₅ represent hydrogen atoms, X₂ represents ahydrogen atom, a fluorine atom or a CF₃ group and Z₂ represents ahydrogen atom or a fluorine atom;

R₁ and R₂ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene or arylgroup; or R₁ and R₂ form, together with the nitrogen atom that bearsthem, an azetidine, pyrrolidine, piperidine, azepine, morpholine,thiomorpholine, piperazine or homopiperazine group, this group beingoptionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene or aryl group;

R₃ and R₄ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl or aryl group;

R₅ represents a C₁-C₆-alkyl or aryl group;

W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;

A represents a 5- to 7-membered heterocycle comprising from one to threeheteroatoms chosen from O, S and N;

the carbon atom(s) of A being optionally substituted with one or moregroups chosen from a hydrogen atom and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl,aryl-C₁-C₆-alkylene, oxo or thio group;

the nitrogen atom(s) of A being optionally substituted with R₆ when thenitrogen is adjacent to a carbon atom substituted with an oxo group, orwith R₇ in the other cases;

R₆ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkyleneor aryl group;

R₇ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkylene,C₁-C₆-alkyl-C(O)—C₃-C₇-cycloalkyl-C₁-C₃-alkylene-(CO)—,C₁-C₆-fluoroalkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, aryl-C(O)—,aryl-C₁-C₆-alkylene-C(O)—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—,C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—,aryl-S(O)₂- or aryl-C₁-C₆-alkylene-S(O)₂— or aryl group; and

W is other than indolyl.

Among the compounds of general formula (I) that are subjects of theinvention, an eighth subgroup of compounds consists of the compounds forwhich W is as defined in the sixth subgroup above and X₁, X₂, X₃, X₄,Z₁, Z₂, Z₃, Z₄ and Z₅ are as defined in the seventh subgroup above.

Among the compounds of general formula (I) that are subjects of theinvention, a ninth subgroup of compounds consists of all of thecompounds of general formula (I):

in which

n is equal to 0, 1, 2 or 3;

X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ and Z₅ represent, independently of eachother, a hydrogen or halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₁R₂, nitro, NR₁R₂, C₁-C₆-thioalkyl,—S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅ oraryl group, the aryl being optionally substituted with one or moresubstituents chosen from a halogen and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, nitro or cyano group;

R₁ and R₂ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene or arylgroup; or R₁ and R₂ form, together with the nitrogen atom that bearsthem, an azetidine, pyrrolidine, piperidine, azepine, morpholine,thiomorpholine, piperazine or homopiperazine group, this group beingoptionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene or aryl group;

R₃ and R₄ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl or aryl group;

R₅ represents a C₁-C₆-alkyl or aryl group;

W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;

A represents a 5- to 7-membered heterocycle comprising from one to threeheteroatoms chosen from O, S and N;

the carbon atom(s) of A being optionally substituted with one or moregroups chosen from a hydrogen atom and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl,aryl-C₁-C₆-alkylene, oxo or thio group;

the nitrogen atom(s) of A being optionally substituted with R₆ when thenitrogen is adjacent to a carbon atom substituted with an oxo group, orwith R₇ in the other cases;

R₆ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkyleneor aryl group;

R₇ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkylene,C₁-C₆-alkyl-C(O)—C₃-C₇-cycloalkyl-C₁-C₃-alkylene-(CO)—,C₁-C₆-fluoroalkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, aryl-C(O)—,aryl-C₁-C₆-alkylene-C(O)—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—,C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—,aryl-S(O)₂- or aryl-C₁-C₆-alkylene-S(O)₂— or aryl group; and

W is other than indolyl,

the following compounds being excluded:N-(quinol-7-yl)-1-benzyl-6-bromo-1H-indole-2-carboxamide,N-(quinol-7-yl)-1-benzyl-5-bromo-1H-indole-2-carboxamide andN-(quinol-7-yl)-6-bromo-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide.These three compounds are described in document US 2005/0165049.

Among the compounds of general formula (I) that are subjects of theinvention, a tenth subgroup of compounds consists of all of thecompounds of general formula (I):

in which

n is equal to 0, 1, 2 or 3;

X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ and Z₅ represent, independently of eachother, a hydrogen or halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₁R₂, nitro, NR₁R₂, C₁-C₆-thioalkyl,—S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅ oraryl group, the aryl being optionally substituted with one or moresubstituents chosen from a halogen and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, nitro or cyano group;

R₁ and R₂ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene or arylgroup; or R₁ and R₂ form, together with the nitrogen atom that bearsthem, an azetidine, pyrrolidine, piperidine, azepine, morpholine,thiomorpholine, piperazine or homopiperazine group, this group beingoptionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene or aryl group;

R₃ and R₄ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl or aryl group;

R₅ represents a C₁-C₆-alkyl or aryl group;

W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;

A represents a 5- to 7-membered heterocycle comprising from one to threeheteroatoms chosen from O, S and N;

the carbon atom(s) of A being optionally substituted with one or moregroups chosen from a hydrogen atom and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl,aryl-C₁-C₆-alkylene, oxo or thio group;

the nitrogen atom(s) of A being optionally substituted with R₆ when thenitrogen is adjacent to a carbon atom substituted with an oxo, or withR₇ in the other cases;

R₆ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkyleneor aryl group;

R₇ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkylene,C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-(CO)—,C₁-C₆-fluoroalkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, aryl-C(O)—,aryl-C₁-C₆-alkylene-C(O)—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—,C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—,aryl-S(O)₂- or aryl-C₁-C₆-alkylene-S(O)₂— or aryl group; and

W is other than indolyl;

on condition that when W is a benzimidazolyl, benzothiazolyl orbenzoxazolyl group, then Z₁, Z₂, Z₃, Z₄ and Z₅ represent a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₁R₂, —S(O)—C₁-C₆-alkyl, SO₂NR₁R₂,NR₃COR₄, NR₃SO₂R₅ or aryl group.

Among the compounds of general formula (I) that are subjects of theinvention, an eleventh subgroup of compounds consists of all of thecompounds of general formula (I):

in which

n is equal to 0, 1, 2 or 3;

X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ and Z₅ represent, independently of eachother, a hydrogen or halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₁R₂, nitro, NR₁R₂, C₁-C₆-thioalkyl,—S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅ oraryl group, the aryl being optionally substituted with one or moresubstituents chosen from a halogen and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, nitro or cyano group;

R₁ and R₂, represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene or arylgroup; or R₁ and R₂ form, together with the nitrogen atom that bearsthem, an azetidine, pyrrolidine, piperidine, azepine, morpholine,thiomorpholine, piperazine or homopiperazine group, this group beingoptionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene or aryl group;

R₃ and R₄ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl or aryl group;

R₅ represents a C₁-C₆-alkyl or aryl group;

W represents a fused bicyclic group of formula:

linked to the nitrogen atom via the positions 1, 2, 3 or 4;

A represents a 5- to 7-membered heterocycle comprising from one to threeheteroatoms chosen from O, S and N;

the carbon atom(s) of A being optionally substituted with one or moregroups chosen from a hydrogen atom and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl,aryl-C₁-C₆-alkylene, oxo or thio group;

the nitrogen atom(s) of A being optionally substituted with R₆ when thenitrogen is adjacent to a carbon atom substituted with an oxo group, orwith R₇ in the other cases;

R₆ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkyleneor aryl group;

R₇ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkylene,C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-(CO)—,C₁-C₆-fluoroalkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, aryl-C(O)—,aryl-C₁-C₆-alkylene-C(O)—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—,C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—,aryl-S(O)₂- or aryl-C₁-C₆-alkylene-S(O)₂— or aryl group; and

W is other than indolyl

on condition that when A is a 5-membered heterocycle, then it isunsaturated.

Among the compounds of general formula (I) that are subjects of theinvention, a twelfth subgroup of compounds consists of all of thecompounds of general formula (I):

in which

n is equal to 0, 1, 2 or 3;

X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ and Z₅ represent, independently of eachother, a hydrogen or halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, cyano, C(O)NR₁R₂, nitro, NR₁R₂, C₁-C₆-thioalkyl,—S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅ oraryl group, the aryl being optionally substituted with one or moresubstituents chosen from a halogen and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy,C₁-C₆-fluoroalkoxy, nitro or cyano group;

R₁ and R₂ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene or arylgroup; or R₁ and R₂ form, together with the nitrogen atom that bearsthem, an azetidine, pyrrolidine, piperidine, azepine, morpholine,thiomorpholine, piperazine or homopiperazine group, this group beingoptionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene or aryl group;

R₃ and R₄ represent, independently of each other, a hydrogen atom or aC₁-C₆-alkyl or aryl group;

R₅ represents a C₁-C₆-alkyl or aryl group;

W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;

A represents a 5- to 7-membered heterocycle comprising from one to threeheteroatoms chosen from O, S and N;

the carbon atom(s) of A being optionally substituted with one or moregroups chosen from a hydrogen atom and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl,aryl-C₁-C₆-alkylene, oxo or thio group;

the nitrogen atom(s) of A being optionally substituted with R₆ when thenitrogen is adjacent to a carbon atom substituted with an oxo group, orwith R₇ in the other cases;

R₆ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkyleneor aryl group;

R₇ represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkylene,C₁-C₆-alkyl-C(O)—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-(CO)—,C₁-C₆-fluoroalkyl-C(O)—, C₃-C₇-cycloalkyl-C(O)—, aryl-C(O)—,aryl-C₁-C₆-alkylene-C(O)—, C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—,C₃-C₇-cycloalkyl-S(O)₂—, C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—,aryl-S(O)₂- or aryl-C₁-C₆-alkylene-S(O)₂— or aryl group; and

W is other than indolyl

on condition that A is other than an unsaturated 5-membered heterocycle.

The compounds for which n, X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄, Z₅ and W areas defined in the above subgroups of compounds form a thirteenthsubgroup.

Among the compounds of general formula (I) that are subjects of theinvention, a fourteenth subgroup of compounds consists of the followingcompounds:

-   N-(isoquinol-5-yl)-5-fluoro-1-[((3-trifluoromethyl)phenyl)methyl]-1H-indole-2-carboxamide,-   N-(1-methyl-1,2,3,4-tetrahydroquinol-7-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(1-methyl-1,2,3,4-tetrahydroquinol-7-yl)-1-((3-5-dimethyl)phenyl)-1H-indole-2-carboxamide,-   N-(1,2,3,4-tetrahydroquinol-7-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(4-methyl-3-oxo-2H-benzoxazin-7-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(4-methyl-3-oxo-2H-benzoxazin-6-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(2-oxo-3,4-dihydroquinol-7-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(benzofuran-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(1-methylindolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(2,3-dihydrobenzoxazin-6-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(3-oxo-2H-benzoxazin-7-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(1-methylindolin-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1-methyl-1,2,3,4-tetrahydroquinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1,2,3,4-tetrahydroquinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(isoquinol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1,2,3,4-tetrahydroquinol-8-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(benzoxazol-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(2-methylbenzoxazol-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,-   N-(1-methyl-1H-indazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-oxo-3,4-dihydroquinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(benzofuran-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2,3-dihydrobenzoxazin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(3-oxo-2H-benzoxazin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1,2,3,4-tetrahydroquinol-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-oxoindolin-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1-methylbenzimidazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1-methyl-1,2,3,4-tetrahydroquinol-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(benzothiazol-6-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-methylbenzoxazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-methylbenzothiazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1-methylsulfonylindolin-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(isoquinol-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1-methylbenzimidazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1-methylbenzimidazol-4-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1H-benzotriazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(quinol-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1-methylindazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-methylbenzoxazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(benzothiazol-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-methylbenzothiazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-oxo-3,4-dihydroquinol-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-oxoindolin-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1H-benzotriazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1-methylsulfonylindolin-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(1,2-dimethylbenzimidazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-ethylbenzoxazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-phenylbenzoxazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(quinoxalin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(quinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(isoquinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-methylbenzimidazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(benzimidazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,-   N-(2-oxo-3,4-dihydroquinol-7-yl)-6-methoxy-1-[(4-fluorophenyl)methyl]-1H-indole-2-carboxamide    and-   N-(1-methylbenzimidazol-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide.

In the context of the present invention, the following meanings apply:

-   -   C_(t)-C_(z) in which t and z may take the values from 1 to 7: a        carbon-based chain possibly containing from t to z carbon atoms,        for example C₁-C₃ is a carbon-based chain that may contain from        1 to 3 carbon atoms;    -   an alkyl: a saturated, linear or branched aliphatic group.        Examples that may be mentioned include methyl, ethyl, propyl,        isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc. groups;    -   an alkylene: a saturated, linear or branched divalent alkyl        group, for example a C₁₋₃-alkylene group represents a linear or        branched divalent carbon-based chain of 1 to 3 carbon atoms,        more particularly a methylene, ethylene, 1-methylethylene or        propylene;    -   a cycloalkyl: a cyclic carbon-based group. Examples that may be        mentioned include cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, etc. groups;    -   a fluoroalkyl: an alkyl group of which one or more hydrogen        atoms have been replaced with a fluorine atom;    -   an alkoxy: a radical —O-alkyl in which the alkyl group is as        defined above;    -   a fluoroalkoxy: an alkoxy group of which one or more hydrogen        atoms have been replaced with a fluorine atom;    -   a thioalkyl: a radical —S-alkyl in which the alkyl group is as        defined above;    -   an aryl: a cyclic aromatic group containing between 6 and 10        carbon atoms. Examples of aryl groups that may be mentioned        include phenyl and naphthyl groups;    -   a heterocycle: a saturated, partially unsaturated or aromatic 5-        to 7-membered cyclic group comprising from one to three        heteroatoms chosen from O, S and N. Examples of groups W that        may be mentioned include indolinyl, isoindolinyl, benzofuryl,        dihydrobenzofuryl, benzothiophenyl, dihydrobenzothiophenyl,        benzoxazolyl, dihydrobenzoxazolinyl, isobenzofuryl,        dihydroisobenzofuryl, benzimidazolyl, dihydrobenzimidazolyl,        indazolyl, benzothiazolyl, isobenzothiazolyl,        dihydroisobenzothiazolyl, benzotriazolyl, quinolyl,        dihydroquinolyl, tetrahydroquinolyl, isoquinolyl,        dihydroisoquinolyl, tetrahydroisoquinolyl, benzoxazinyl,        dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl,        cinnolinyl, quinazolinyl, dihydroquinazolinyl,        tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl,        tetrahydroquinoxalinyl, phthalazinyl, dihydrophthalazinyl,        tetrahydrophthalazinyl, tetrahydrobenz[b]azepinyl,        tetrahydrobenz[c]azepinyl, tetrahydrobenz[d]azepinyl,        tetrahydrobenz[d]azepinyl, tetrahydrobenzo[b][1,4]diazepinyl,        tetrahydrobenzo[e][1,4]diazepinyl,        tetrahydrobenzo[b][1,4]oxazepinyl and        tetrahydrobenzo[b][1,4]thiazepinyl groups;    -   a halogen atom: a fluorine, a chlorine, a bromine or an iodine;    -   “oxo” means “═O”;    -   “thio” means “═S”.

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may thus exist in the form of enantiomers ordiastereoisomers.

These enantiomers and diastereoisomers, and also mixtures thereof,including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or ofacid-addition salts. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids that are useful, for example, forpurifying or isolating the compounds of formula (I) also form part ofthe invention.

The compounds of general formula (I) may be in the form of hydrates orsolvates, i.e. in the form of associations or combinations with one ormore water molecules or with a solvent. Such hydrates and solvates alsoform part of the invention.

In the text hereinbelow, the term “leaving group” means a group that canbe readily cleaved from a molecule by breaking a heterolytic bond, withloss of an electron pair. This group may thus be readily replaced withanother group, for example during a substitution reaction. Such leavinggroups are, for example, halogens or an activated hydroxyl group such asa methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate,acetate, etc. Examples of leaving groups and references for preparingthem are given in “Advances in Organic Chemistry”, J. March, 5^(th)Edition, Wiley Interscience, 2001.

In accordance with the invention, the compounds of general formula (I)may be prepared according to the process illustrated in scheme 1 below.

According to scheme 1, the compounds of general formula (IV) may beobtained by reacting a compound of general formula (II) in which X₁, X₂,X₃ and X₄ are as defined in the general formula (I) above and Brepresents a C₁-C₆-alkoxy or hydroxyl group, with a compound of generalformula (III), in which Z₁, Z₂, Z₃, Z₄, Z₅ and n are as defined in thegeneral formula (I) above and R′ represents a bromine or iodine atom, atosylate group or any other leaving group.

When n=1, 2 or 3, the compound of general formula (III) may be an alkylhalide, such as a benzyl bromide (n=1: Kolasa T., Bioorg. Med. Chem.1997, 5 (3) 507) or a phenethyl iodide (n=2: Abramovitch R., Synth.Commun., 1995, 25 (1), 1), and the reaction may be performed in thepresence of a base such as sodium hydride or potassium carbonate, in apolar solvent such as dimethylformamide, dimethyl sulfoxide or acetone.

When n=0, the compound of general formula (III) is an aryl iodide orbromide and the reaction may be performed at a temperature of between80° C. and 250° C., in the presence of a copper-based catalyst such ascopper bromide or copper oxide and also a base such as potassiumcarbonate (Murakami Y., Chem. Pharm. Bull., 1995, 43 (8), 1281). Themilder conditions described in S. L. Buchwald, J. Am. Chem. Soc. 2002,124, 11684 may also be used.

Alternatively, the compounds of general formula (IV), in which n=0, maybe obtained by reacting the compound of general formula (II) with acompound of general formula (III) of boronic acid type (n=0, R′=B(OH)₂),in the presence of a base such as triethylamine or pyridine and alsocopper diacetate, by analogy with protocols described in W. W. K. R.Mederski, Tetrahedron, 1999, 55, 12757.

The compounds of general formula (II) are commercially available orprepared according to many processes described in the literature (forexample D. Knittel Synthesis 1985, 2, 186; T. M. Williams J. Med. Chem.1993, 36 (9), 1291; JP2001151771A2).

In the case of the indoles of general formula (IV), in which Brepresents a C₁-C₆-alkoxy group, the compound of general formula (I) isobtained by reacting a compound of general formula (IV), as obtainedabove, with an amide of the compound of general formula (V), in which Wis as defined in the general formula (I) above, at the reflux point of asolvent such as toluene. The amide of the compound of general formula(V) is prepared by the prior action of trimethylaluminum on the aminesof general formula (V).

In the case of the indoles of general formula (IV), in which Brepresents a hydroxyl group, the carboxylic acid function may beconverted beforehand into an acid halide such as an acid chloride viathe action of thionyl chloride, at the reflux point of a solvent such asdichloromethane or dichloroethane. The compound of general formula (I)is then obtained by reacting the compound of general formula (IV), inwhich B represents a chlorine atom, with the compound of general formula(V), in the presence of a base such as triethylamine or sodiumcarbonate.

Alternatively, the indole of general formula (IV), in which B representsa hydroxyl group, may be coupled with the compound of general formula(V) in the presence of a coupling agent such as a dialkyl carbodiimide,benzotriazol-1-yloxytris(pyrrolidinophosphonium) hexafluorophosphate,diethyl cyanophosphonate or any other coupling agent known to thoseskilled in the art, in the presence of a base such as triethylamine, ina solvent such as dimethylformamide.

In scheme 1, the compounds of formula (II), (III) and (V) and the otherreagents, when their preparation method is not described, arecommercially available or described in the literature (for example WO2003/049702 or WO 2003/068749).

The compounds of general formulae (II), (IV) and (I), in which X₁, X₂,X₃, X₄, Z₁, Z₂, Z₃, Z₄ and/or Z₅ represent a cyano group or an aryl, maybe obtained via a coupling reaction, catalyzed with a metal such aspalladium, performed on the corresponding compounds of general formula(II), (IV) or (I), in which X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ and/or Z₅represents a bromine atom.

The compounds of general formulae (II), (IV) and (I), in which X₁, X₂,X₃, X₄, Z₁, Z₂, Z₃, Z₄ and/or Z₅ represent a group C(O)NR₁R₂, may beobtained from the corresponding compounds of general formula (II), (IV)or (I), in which X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ and/or Z₅ represents acyano group, according to methods that are described in the literatureor that are known to those skilled in the art.

The compounds of general formulae (II), (IV) and (I), in which X₁, X₂,X₃, X₄, Z₁, Z₂, Z₃, Z₄ and/or Z₅ represent a group —S(O)-alkyl or—S(O)₂-alkyl, may be obtained by oxidation of the correspondingcompounds of general formula (II), (IV) or (I), in which X₁, X₂, X₃, X₄,Z₁, Z₂, Z₃, Z₄ and/or Z₅ represents a C₁-C₆-thioalkyl group, accordingto methods that are described in the literature or that are known tothose skilled in the art.

The compounds of general formulae (II), (IV) and (I), in which X₁, X₂,X₃, X₄, Z₁, Z₂, Z₃, Z₄ and/or Z₅ represent a group NR₁R₂, NR₃COR₄ orNR₃SO₂R₅, may be obtained from the corresponding compounds of generalformula (II), (IV) or (I), in which X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄and/or Z₅ represents a nitro group, for example by reduction, followedby acylation or sulfonylation, according to methods that are describedin the literature or that are known to those skilled in the art.

The compounds of general formulae (II), (IV) and (I), in which X₁, X₂,X₃, X₄, Z₁, Z₂, Z₃, Z₄ and/or Z₅ represent a group SO₂NR₁R₂, may beobtained via a method analogous to that described in Pharmazie 1990, 45,346, or according to methods that are described in the literature orthat are known to those skilled in the art.

The compounds of general formula (I) in which R₇ represents a hydrogenatom may be obtained from compounds of general formula (I) in which R₇represents a phenylmethyl group, by hydrogenation, for example catalyzedwith palladium, or by any method described in the literature or known tothose skilled in the art. The examples that follow describe thepreparation of certain compounds in accordance with the invention. Theseexamples are not limiting and serve merely to illustrate the presentinvention. The numbers of the compounds given as examples refer to thosegiven in Table 1. The elemental microanalyses, the LC-MS (liquidchromatography coupled to mass spectrometry) analyses and the IR and NMRspectra confirm the structures of the compounds obtained.

EXAMPLE 1 (Compound 12)N-(1-methyl-1H-indolin-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide1.1. Ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate

A suspension of 0.207 g (1 mmol) of ethyl5-fluoro-1H-indole-2-carboxylate, 0.173 g (1.2 mmol) of 3-fluorobenzylchloride and 0.276 g (2 mmol) of potassium carbonate in 10 ml ofdimethylformamide is stirred for 24 hours at 60° C. The reaction mixtureis then cooled and poured into a mixture of ice-water and ethyl acetate.After allowing the phases to separate by settling, the organic phase isseparated out and then washed with twice 50 ml of water and then with 50ml of saturated sodium chloride solution. The solution is dried overmagnesium sulfate and filtered, and the filtrate is then concentratedunder reduced pressure. 0.195 g of an oil is obtained, which is usedwithout further purification in the following step.

1.2N-(1-methyl-1H-indolin-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide(compound 12)

0.089 g (0.6 mmol) of 5-amino-1-methyl-1H-indoline (WO 2003/049702) and0.5 ml of trimethylaluminum (2M in toluene) are added to 2 ml of tolueneunder argon. The mixture is heated for 2 hours at 50° C. and 0.157 g(0.5 mmol) of ethyl5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained instep 1.1, is added. The reaction medium is refluxed for 10 minutes andleft at room temperature overnight. It is poured onto ice and 1 ml of 1Nhydrochloric acid is added. The resulting mixture is extracted withethyl acetate and the organic phase is dried with magnesium sulfate andconcentrated under reduced pressure. The residue is purified bypreparative chromatography. 0.066 g of solid is obtained.

Melting point: 145-147° C.

¹H NMR (DMSO D₆), δ (ppm): 2.65 (s, 3H); 2.85 (t, 2H); 3.2 (t, 2H); 5.85(s, 2H); 6.45 (d, 1H); 6.9 (m, 2H); 7.1 (m, 2H); 7.3 (m, 3H); 7.5 (m,3H);

EXAMPLE 2 (Compound 13)N-(1-methyl-1,2,3,4-tetrahydroquinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

The process is performed according to the method described in step 1.2of Example 1, starting with 0.185 g of7-amino-1-methyl-1,2,3,4-tetrahydroquinol (WO 2003/049702), 0.95 ml oftrimethylaluminum (2M in toluene) and 0.3 g of is ethyl5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained instep 1.1 of Example 1. 0.122 g of product is obtained.

Melting point: 159-160° C.

¹H NMR (DMSO D₆): δ (ppm): 1.85 (m, 2H); 2.65 (t, 2H); 2.8 (s, 3H); 3.15(t, 2H); 5.85 (s, 2H); 7 (m, 7H); 7.3 (m, 2H); 7.5 (m, 2H); 10.1 (s, 1H)

EXAMPLE 3 (Compound 14)N-(1,2,3,4-tetrahydroquinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

The process is performed according to the method described in step 1.2of Example 1, starting with 0.169 g of 7-amino-1,2,3,4-tetrahydroquinol(WO 2003/049702), 0.95 ml of trimethylaluminum (2M in toluene) and 0.3 gof ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate,obtained in step 1.1 of Example 1. 0.033 g of product is obtained.

Melting point: 149-151° C.

¹H NMR (DMSO D₆): δ (ppm): 1.75 (m, 2H); 2.6 (t, 2H); 3.1 (t, 2H); 5.85(s, 2H); 6.95 (m, 7H); 7.3 (m, 2H); 7.5 (m, 2H); 10.1 (s, 1H)

EXAMPLE 4 (Compound 18)N-(2-methyl-benzoxazol-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide

0.091 ml (0.6 mmol) of diethylcyanophosphonate, 0.168 ml (0.6 mmol) oftriethylamine and 0.111 g (0.6 mmol) of 5-amino-2-methylbenzoxazolehydrochloride are added to a solution of 0.152 g (0.5 mmol) of1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxylic acid(JP2001151771A2) in 3 ml of dimethylformamide. The mixture is stirredovernight at room temperature and concentrated under reduced pressure,and the residue is taken up in water and dichloromethane. Afterseparation of the phases by settling, the organic phase is dried andevaporated under reduced pressure. The residue is purified bypreparative chromatography. 0.102 g of solid is obtained.

Melting point: 223-225° C.

¹H NMR (DMSO D₆): δ (ppm): 2.55 (s, 3H); 7.2 (m, 3H); 7.6 (m, 3H); 7.75(m, 5H); 7.95 (s, 1H); 10.5 (s, 1H)

EXAMPLE 5 (Compound 19)N-(1-methyl-1H-indazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide5.1 Ethyl5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate

A solution of 2.88 g (11.2 mmol) of ethyl5-trifluoromethyl-1H-indole-2-carboxylate (obtained by Fisher indolesynthesis from 4-(trifluoromethyl)phenylhydrazine) in 50 ml ofdimethylformamide is added dropwise to a suspension of 0.58 g (14.56mmol) of sodium hydride in 5 ml of dimethylformamide cooled in an icebath. The mixture is stirred for 2 hours at room temperature and asolution of 2.54 g (13.44 mmol) of 3-fluorobenzyl bromide in 20 ml ofdimethylformamide is then added. Stirring is continued for 24 hours.2.44 mmol of 3-fluorobenzyl bromide are added and the mixture is stirredfor a further 4 hours. The solvent is evaporated off under reducedpressure and the residue is taken up in water and ethyl acetate. Afterseparation of the phases by settling, the organic phase is separated outand then washed with twice 50 ml of water and then with 50 ml ofsaturated sodium chloride solution. The solution is dried over magnesiumsulfate and filtered, and then the filtrate is concentrated underreduced pressure. The residue is purified by chromatography on silicagel. 2.74 g of product are obtained.

5.2.N-(1-methyl-1H-indazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

A solution of 0.34 g (2.3 mmol) of 5-amino-1-methyl-1H-indazole (I. T.Forbes, J. Med. Chem. 1993, 36 (8), 1104) in 10 ml of toluene is added,on an ice bath, to a solution of 1.92 ml (3.83 mmol) oftrimethylaluminum (2M in toluene) in 5 ml of toluene. The reactionmedium is maintained at 50° C. for 30 minutes. 1.92 mmol of ethyl5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate,obtained in step 5.1, dissolved in 10 ml of toluene, is then added. Themixture is refluxed for 3 hours and allowed to cool to room temperature.20 ml of water and 30 ml of ethyl acetate are added. The aqueous phaseis extracted with ethyl acetate; the organic phases are combined andwashed with water and then with saturated sodium chloride solution. Thesolution is dried over magnesium sulfate and filtered, and the filtrateis then concentrated under reduced pressure. The residue is purified bychromatography on a column of silica, eluting with a mixture of ethylacetate and dichloromethane. The residue is taken up in petroleum ether,filtered, rinsed and dried under reduced pressure. 0.71 g of solid isobtained.

Melting point: 198-199° C.

¹H NMR (CDCl₃): δ (ppm): 4 (s, 3H); 5.9 (s, 2H); 6.9 (m, 2H); 7 (m, 1H);7.3 (m, 1H); 7.6 (m, 4H); 7.8 (d, 1H); 8 (s, 1H); 8.2 (d, 2H); 10.6 (s,1H).

EXAMPLE 6 (Compound 20)N-(1H-2-oxo-3,4-dihydroquinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

0.097 g (0.6 mmol) of 7-amino-1H-3,4-dihydroquinol-2-one (WO2003/049702) and 0.5 ml of trimethylaluminum (2M in toluene) are addedto 2 ml of toluene under argon. The mixture is heated for 2 hours at 50°C. and 0.157 g (0.5 mmol) of ethyl5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained instep 1.1 of Example 1, dissolved in 1 ml of toluene, is added. Thereaction medium is refluxed for 2 hours and left at room temperatureovernight. It is poured onto ice and 2 ml of 1N hydrochloric acid areadded. The resulting mixture is extracted with ethyl acetate and theorganic phase is dried with magnesium sulfate and concentrated underreduced pressure. The residue is purified by preparative chromatography.0.047 g of solid is obtained.

Melting point: 277-279° C.

¹H NMR (DMSO D₆): δ (ppm): 2.4 (t, 2H); 2.8 (t, 2H); 5.85 (s, 2H); 6.9(m, 2H) 7.1 (m, 5H); 7.4 (m, 2H); 7.5 (m, 2H); 10.05 (s, 1H); 10.4 (s,1H)

EXAMPLE 7 (Compound 22)N-(2,3-dihydrobenzoxazin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

The process is performed according to the method described in Example 6,starting with 0.090 g of 6-amino-2,3-dihydrobenzoxazine (WO2003/049702), 0.5 ml of trimethylaluminum (2M in toluene) and 0.157 g ofethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate,obtained in step 1.1 of Example 1. 0.061 g of product is obtained.

Melting point: 216-217° C.

¹H NMR (DMSO D₆): δ (ppm): 3.25 (t, 2H); 4.1 (t, 2H); 5.85 (s, 2H+1H);6.55 (d, 1H); 6.9 (m, 3H); 7.1 (m, 3H); 7.3 (m, 2H); 7.5 (m, 2H); 10.1(s, 1H)

EXAMPLE 8 (Compound 23)N-(3-oxo-2H-benzoxazin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

The process is performed according to the method described in Example 6,starting with 0.107 g of 6-amino-3-oxo-2H-benzoxazine (WO 2003/049702),0.5 ml of trimethylaluminum (2M in toluene) and 0.157 g of ethyl5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained instep 1.1 of Example 1. 0.053 g of product is obtained.

LC-MS: M+H=434

¹H NMR (DMSO D₆): δ (ppm): 4.5 (s, 2H); 5.85 (s, 2H); 6.9 (m, 3H); 7.1(m, 4H); 7.4 (s, 1H); 7.5 (m, 3H); 10.4 (s, 1H); 10.7 (s, 1H)

EXAMPLE 9 (Compound 24)N-(1,2,3,4-tetrahydroquinol-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

A solution of 0.24 g (1.64 mmol) of 7-amino-1,2,3,4-tetrahydroquinol (WO2003/049702) in 5 ml of toluene is added, at 0° C. on an ice bath, to asolution of 1.37 ml (2.74 mmol) of trimethylaluminum (2M in toluene) in5 ml of toluene. The reaction medium is maintained at 50° C. for 2hours. 0.5 g (1.37 mmol) of ethyl5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate,obtained in step 5.1 of Example 5, dissolved in 10 ml of toluene, isthen added. The mixture is refluxed for 3 hours and allowed to cool toroom temperature. 20 ml of ice-water, 20 ml of ethyl acetate and 20 mlof 1N hydrochloric acid are added. After filtering the mixture andseparation of the phases by settling, the organic phase is washed withan alkaline solution and then with saturated sodium chloride solution.The organic phase is dried over magnesium sulfate and filtered, and thefiltrate is then concentrated under reduced pressure. The residue istaken up in petroleum ether, collected by filtration and dried underreduced pressure. The product is purified by chromatography on a columnof silica, eluting with a mixture of heptane and dichloromethane. Theresidue is recrystallized from ethanol. 0.29 g of solid is obtained.

Melting point: 203-204° C.

¹H NMR (DMSO): δ (ppm): 1.7 (m, 2H); 2.6 (m, 2H); 3.1 (m, 2H); 5.7 (t,1H); 5.9 (s, 2H); 6.7 (m, 2H); 6.95 (m, 4H); 7.3 (m, 1H); 7.45 (s, 1H);7.5 (d, 1H); 7.75 (d, 1H); 8.1 (s, 1H); 10.2 (s, 1H).

EXAMPLE 10 (Compound 26)N-(1-methyl-benzimidazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide10.1 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylicacid

A solution of 0.7 g (1.92 mol) of ethyl5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate,obtained in step 5.1 of Example 5, and 0.21 g (3.83 mmol) of potassiumhydroxide in 10 ml of methanol is heated to reflux. The mixture isconcentrated under reduced pressure and the residue is taken up in waterand acidified with hydrochloric acid. The precipitate is collected byfiltration, rinsed with water and dried under reduced pressure. 0.69 gof solid is obtained, and is used without further purification in thefollowing step.

10.2N-(1-methyl-benzimidazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

A solution of 0.32 g (0.95 mmol) of5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylicacid, obtained in step 10.1, and 0.69 ml (9.49 mmol) of thionyl chloridein 25 ml of dichloromethane is refluxed for 2 hours. The mixture isconcentrated under reduced pressure, the residue is taken up in 20 ml ofdiethyl ether, and 0.17 g (1.14 mmol) of 5-amino-1-methylbenzimidazoleand a solution of 0.2 g (1.9 mmol) of sodium carbonate in 2 ml of waterare added. The mixture is stirred for 24 hours at room temperature, theorganic phase is evaporated under reduced pressure and the resultingphase is extracted with ethyl acetate and dichloromethane. The organicphases are washed with water and with saturated sodium chloridesolution, dried over sodium sulfate and concentrated under reducedpressure. The residue is taken up in petroleum ether, collected byfiltration, washed and dried under reduced pressure. It is then purifiedby chromatography on a column of silica gel, eluting with a mixture ofdichloromethane and ethyl acetate. The residue is taken up in petroleumether, collected by filtration, washed and dried under reduced pressure.0.3 g of solid is obtained.

Melting point: 223-224° C.

¹H NMR (DMSO), δ (ppm): 5.9 (s, 2H); 7 (m, 3H); 7.3 (m, 1H); 7.55 (m,4H); 7.8 (d, 1H); 8.05 (s, 1H); 8.1 (d, 2H); 10.5 (s, 1H).

EXAMPLE 11 (Compound 49)N-(quinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide11.1 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid

A solution of 8.3 g (26.3 mmol) of ethyl5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained instep 1.1 of Example 1, and 5.2 g (79 mmol) of potassium hydroxide in asolution of 140 ml of ethanol and 14 ml of water is refluxed for 2hours. The mixture is concentrated under reduced pressure and theresidue is taken up in water and acidified with hydrochloric acid. Theprecipitate is collected by filtration, rinsed with water and driedunder reduced pressure. 7.4 g of solid are obtained, and are usedwithout further purification in the following step.

Melting point: 205-206° C.

11.2N-(quinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

1 g (1.9 mmol) of benzotriazol-1-yloxytris(pyrrolidine)phosphoniumhexafluorophosphate is added, with stirring and under nitrogen, to asuspension of 0.5 g (1.74 mmol) of5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid,obtained in step 11.1, in 10 ml of dry dimethylformamide. After 5minutes, 0.4 g (1.83 mmol) of 7-aminoquinoline hydrochloride (WO2003/049702) and 0.9 g (7 mmol) of diisopropylethylamine are added.After stirring for 2 hours at room temperature and for 2 hours at 60°C., the reaction medium is poured into 100 ml of water and 50 ml ofethyl acetate. After separation of the phases by settling and extractionof the aqueous phase, the organic phases are combined, washed with waterand dried over sodium sulfate. The residue is purified by chromatographyon a column of silica gel, eluting with a mixture of dichloromethane andacetone. The solid obtained is recrystallized from isopropyl alcohol.0.26 g of solid is obtained.

Melting point: 222-223° C.

¹H NMR (DMSO), δ (ppm): 5.95 (s, 2H); 6.95 (t, 2H); 7.05 (m, 1H); 7.2(t, 1H); 7.35 (q, 1H); 7.45 (m, 1H); 7.55 (s, 1H); 7.65 (m, 2H); 8 (s,2H); 8.3 (d, 1H); 8.55 (s, 1H); 8.9 (m, 1H); 11 (s, 1H).

Table 1 below illustrates the chemical structures and the physicalproperties of a number of compounds of general formula (I) according tothe invention. In this table, the “m.p.” column gives the melting pointsof the products in degrees Celsius (° C.). When the products wereisolated in the form of an amorphous solid or an oil, they arecharacterized in this column by their mass ([MH]⁺). Moreover, in the“salt” column, “-” represents a compound in free base form, whereas“HCl” represents a compound in hydrochloride form, and the ratio inparentheses is the (acid:base) ratio TABLE 1 (I)

No. X₁, X₂, X₃, X₄ n Z₁, Z₂, Z₃, Z₄, Z₅ W m.p. (° C.) Salt 1 H, F, H, H1 H, CF₃, H, H, isoquinol-5-yl 208-209 — H 2 H, H, H, H 0 H, CF₃, H, H,1-methyl-1,2,3,4- 92-95 — H tetrahydroquinol-7-yl 3 H, H, H, H 0 H, CH₃,H, 1-methyl-1,2,3,4- 176-178 — CH₃, H tetrahydroquinol-7-yl 4 H, H, H, H0 H, CF₃, H, H, 1,2,3,4- 140-143 — H tetrahydroquinol-7-yl 5 H, H, H, H0 H, CF₃, H, H, 4-methyl-3-oxo-2H- 198-200 — H benzoxazin-7-yl 6 H, H,H, H 0 H, CF₃, H, H, 4-methyl-3-oxo-2H- 178-180 — H benzoxazin-6-yl 7 H,H, H, H 0 H, CF₃, H, H, 2-oxo-3,4- [MH]⁺ = — H dihydroquinol-7-yl 450 8H, H, H, H 0 H, CF₃, H, H, benzofuran-5-yl 141-143 — H 9 H, H, H, H 0 H,CF₃, H, H, 1-methylindolin-5-yl [MH]⁺ = — H 436 10 H, H, H, H 0 H, CF₃,H, H, 2,3-dihydro- 90-92 — H benzoxazin-6-yl 11 H, H, H, H 0 H, CF₃, H,H, 3-oxo-2H-benzoxazin- 214-216 — H 7-yl 12 H, F, H, H 1 H, F, H, H, H1-methylindolin-5-yl 145-147 — 13 H, F, H, H 1 H, F, H, H, H1-methyl-1,2,3,4- 159-160 — tetrahydroquinol-7-yl 14 H, F, H, H 1 H, F,H, H, H 1,2,3,4- 149-151 — tetrahydroquinol-7-yl 15 H, F, H, H 1 H, F,H, H, H isoquinol-5-yl 206-207 — 16 H, H, H, H 0 H, CF₃, H, H, 1,2,3,4-93-95 — H tetrahydroquinol-8-yl 17 H, H, H, H 0 H, CF₃, H, H,benzoxazol-5-yl 222-224 — H 18 H, H, H, H 0 H, CF₃, H, H,2-methylbenzoxazol- 223-225 — H 5-yl 19 H, CF₃, H, 1 H, F, H, H, H1-methylindazol-5-yl 198-199 — H 20 H, F, H, H 1 H, F, H, H, H2-oxo-3,4- 277-279 — dihydroquinol-7-yl 21 H, F, H, H 1 H, F, H, H, Hbenzofuran-5-yl [MH]⁺ = — 403 22 H, F, H, H 1 H, F, H, H, H 2,3-dihydro-216-217 — benzoxazin-6-yl 23 H, F, H, H 1 H, F, H, H, H3-oxo-2H-benzoxazin- [MH]⁺ = — 6-yl 434 24 H, CF₃, H, 1 H, F, H, H, H1,2,3,4- 203-204 — H tetrahydroquinol-7-yl 25 H, CF₃, H, 1 H, F, H, H, H2-oxoindolin-5-yl 244-246 — H 26 H, CF₃, H, 1 H, F, H, H, H 1-methyl-223-224 — H benzimidazol-5-yl 27 H, CF₃, H, 1 H, F, H, H, H1-methyl-1,2,3,4- 146-147 — H tetrahydroquinol-7-yl 28 H, CF₃, H, 1 H,F, H, H, H benzothiazol-6-yl 191-192 — H 29 H, CF₃, H, 1 H, F, H, H, H2-methylbenzoxazol- 182-183 — H 5-yl 30 H, CF₃, H, 1 H, F, H, H, H2-methylbenzothiazol- 191-192 — H 5-yl 31 H, CF₃, H, 1 H, F, H, H, H 1-214-215 — H methylsulfonylindolin- 5-yl 32 H, F, H, H 1 H, F, H, H, Hisoquinol-6-yl 139-141 — 33 H, F, H, H 1 H, F, H, H, H 1-methyl- 248-251— benzimidazol-5-yl 34 H, F, H, H 1 H, F, H, H, H 1-methyl- 195-197 —benzimidazol-4-yl 35 H, CF₃, H, 1 H, F, H, H, H 1H-benzotriazol-5-yl167-174 — H 36 H, F, H, H 1 H, F, H, H, H quinol-6-yl 208-210 — 37 H, F,H, H 1 H, F, H, H, H 1-methylindazol-5-yl 210-211 — 38 H, F, H, H 1 H,F, H, H, H 2-methylbenzoxazol- 188-189 — 5-yl 39 H, F, H, H 1 H, F, H,H, H benzothiazol-6-yl 167-168 — 40 H, F, H, H 1 H, F, H, H, H2-methylbenzothiazol- 201-202 — 5-yl 41 H, CF₃, H, 1 H, F, H, H, H2-oxo-3,4- 298-299 — H dihydroquinol-7-yl 42 H, F, H, H 1 H, F, H, H, H2-oxoindolin-5-yl 249-250 — 43 H, F, H, H 1 H, F, H, H, H1H-benzotriazol-5-yl 220-221 — 44 H, F, H, H 1 H, F, H, H, H 1-methyl-192-193 — sulfonylindolin-5-yl 45 H, F, H, H 1 H, F, H, H, H1,2-dimethyl- 281-282 — benzimidazol-5-yl 46 H, CF₃, H, 1 H, F, H, H, H2-ethylbenzoxazol-5- 187-189 — H yl 47 H, CF₃, H, 1 H, F, H, H, H2-phenylbenzoxazol- 194-195 — H 5-yl 48 H, F, H, H 1 H, F, H, H, Hquinoxalin-6-yl 188-189 — 49 H, F, H, H 1 H, F, H, H, H quinol-7-yl222-223 — 50 H, F, H, H 1 H, F, H, H, H isoquinol-7-yl 270-272 HCl (1:1)51 H, F, H, H 1 H, F, H, H, H 2-methyl- 195-200 HCl benzimidazol-5-yl(1:1) 52 H, F, H, H 1 H, F, H, H, H benzimidazol-5-yl 275-280 HCl (1:1)53 H, H, 1 H, H, F, H, H 2-oxo-3,4- 255-256 — CH₃O, H dihydroquinol-7-yl54 H, F, H, H 1 H, F, H, H, H 1-methyl- 215-216 — benzimidazol-6-yl

The compounds of the invention were subjected to in vitro and in vivopharmacological tests that demonstrated their value as substances withtherapeutic activities.

Test of Inhibition of the Current Induced with Capsaicin on Rat DRGs

Primary Culture of Rat Dorsal Root Ganglion (DRG) Cells:

The neurons of the DRG naturally express the TRPV1 receptor.

The primary cultures of newborn rat DRGs are prepared using 1-day-oldrats. Briefly, after dissection, the ganglions are trypsinized and thecells dissociated by mechanical trituration. The cells are resuspendedin an Eagle basal culture medium containing 10% fetal calf serum, 25 mMKCl, 2 mM glutamine, 100 μg/ml gentamicin and 50 ng/ml of NGF, and thendeposited on glass slides coated with laminin (0.25×10⁶ cells perslide), which are then placed in Corning 12-well dishes. The cells areincubated at 37° C. in a humidified atmosphere containing 5% CO₂ and 95%air. Cytosine β-D-arabinoside (1 μM) is added 48 hours after culturing,to prevent the growth of non-neuronal cells. The slides are transferredinto experimental chambers for the patch-clamp studies after 7-10 daysof culturing.

Electrophysiology

The measuring chambers (volume 800 μl) containing the cell preparationare placed on the platform of an inverted microscope (Olympus IMT2)equipped with Hoffman optics (Modulation Contrast, N.Y.) and observed ata magnification of 400×. The chambers are continuously gravity-influxed(2.5 ml/min) using a solution distributor accepting 8 inlets and whosesole outlet, consisting of a polyethylene tube (aperture 500 μm), isplaced less than 3 mm from the cell under study. The “whole cell”configuration of the patch-clamp technique was used. Theborosilicate-glass pipettes (resistance 5-10 MOhms) are brought to thecell by means of a 3D piezoelectric micromanipulator (Burleigh, PC1000).The overall currents (membrane potential set at −60 mV) are recordedwith an Axopatch 1D amplifier (Axon Instruments, Foster city, Calif.),connected to a PC running the Pclamp8 software (Axon Instrument). Thecurrent plots are recorded on paper and simultaneously digitized(sampling frequency 15 to 25 Hz) and acquired on the hard drive of thePC.

The application of a 300 nM capsaicin solution induces on the DRG cells(voltage set at −70 mV) an entering cationic current. In order tominimize the desensitization of the receptors, a minimum interval of 1minute between two applications of capsaicin is observed. After acontrol period (stabilization of the capsaicin response alone), the testcompounds are applied alone at a given concentration (concentration of10 nM or 1 nM) for a time of 4 to 5 minutes, during which severalcapsaicin+compound tests are performed (to obtain the maximuminhibition). The results are expressed as a percentage of inhibition ofthe control capsaicin response.

The percentages of inhibition of the capsaicin response (300 nM) arebetween 20% and 100% for the most active antagonist compounds of theinvention tested at a concentration of 10 nM or 1 nM (see selectedexamples in Table 2). TABLE 2 Compound No. % inhibition in DRG patch 1438% (10 nM) 19 48% (1 nM) 20 45% (1 nM)

The intrinsic agonist effect of the compounds may be evaluated bymeasuring the current induced at various compound concentrations on therat DRG, in the presence or absence of capsazepine.

Test of Mouse Corneal Irritation

The irritant nature of capsaicin is readily assessed on the cornea sincethis organ is one of the organs most densely innervated with C fibres.In this context, from preliminary experiments, the application of a verysmall amount of capsaicin (2 μl at a concentration of 160 μM) to thesurface of the cornea of an animal leads to a certain number ofstereotypic behavioral traits associated with irritation, which are easyto detect. Among these, the following are noted: blinking of the eye,rubbing of the instilled eye with the ipsilateral front paw, rubbing ofthe face with both front paws, scratching of the ipsilateral face withthe hind paw. The duration of this behavior does not exceed the 2minutes of observation, and the animal then resumes its normal activity.This aspect is moreover also normal. The mouse is not recluse in acorner with raised hackles and does not develop any observable sign ofsuffering. It may be concluded that the duration of action of capsaicinat these doses is less than 2 minutes.

Summary of the Methodology:

The principle of the series of experiments is to determine whether thecompounds of the invention can influence the behavioral response inducedwith a given amount of capsaicin. The capsaicin is initially diluted to25 mM in DMSO and diluted, for its final use, in Tween 80 to 10% inphysiological saline. It appears, from control studies, that, underthese conditions, the solvent has no effect.

In practice, the test product is administered orally and, with a delay(pretreatment time: t) that depends on the pharmacokinetic data, theanimal receives an ocular instillation of 2 μl of a 160 μM capsaicinsolution prepared as indicated above. During a 2-minute observationfollowing the instillation, the number of times the instilled eye isrubbed with the ipsilateral front paw is recorded.

For a given animal, the percentage of protection is calculated asfollows:P=100−((number of scratching actions observed/mean number of scratchingactions for the group treated with the solvent)×100)This percentage of protection is averaged for each group of animals(n=number of animals tested with the compound of the invention).

The percentages of protection evaluated in this model for the mostactive compounds of the invention, used at a dose of 1 mg/kg (po), arebetween 20% and 100% (see selected examples in Table 3): TABLE 3Compound % P - (t) at 1 mg/kg No. (po) - (n = 8) 14 46% - (1h) 20 26% -(1h)

The results of these tests show that the compounds may have agonist orantagonist effects on the TRPV1 receptor. The most active antagonistcompounds of the invention block the effects induced by stimulation ofthe TRPV1 receptors.

The compounds of the invention may thus be used for the preparation ofmedicaments, especially for the preparation of a medicament forpreventing or treating pathologies in which the TRPV1 receptors areinvolved.

Thus, according to another of its aspects, a subject of the invention ismedicaments that comprise a compound of formula (I), or apharmaceutically acceptable salt, or alternatively a hydrate or asolvate of the said compound.

These medicaments find therapeutic use especially in the preventionand/or treatment of pain and inflammation, chronic pain, neuropathicpain (trauma-related, diabetic, metabolic, infection-related or toxicpain, or pain induced by an anticancer or iatrogenic treatment),(osteo)arthritic pain, rheumatic pain, fibromyalgia, back pain,cancer-related pain, facial neuralgia, headaches, migraine, dental pain,burns, sunburn, animal bites or insect bites, post-herpetic neuralgia,muscular pain, trapped nerves (central and/or peripheral), spinal columnand/or brain trauma, ischemia (of the spinal column and/or the brain),neurodegeneration, hemorrhagic strokes (of the spinal column and/or ofthe brain) and post-stroke pain.

The compounds of the invention may be used for the preparation of amedicament for preventing and/or treating urological disorders such ashyperactivity of the bladder, vesical hyperreflexia, vesicalinstability, incontinence, urgent micturition, urinary incontinence,cystitis, nephritic colic, pelvic hypersensitivity and pelvic pain.

The compounds of the invention may be used to prepare a medicament forpreventing and/or treating gynecological disorders, for instancevulvodynia and pain associated with salpingitis or with dysmenorrhea.

These products may also be used for the preparation of a medicament forpreventing and/or treating gastrointestinal disorders such as gastroesophageal reflux disorder, stomach ulcers, duodenal ulcers, functionaldyspepsia, colitis, IBS, Crohn's disease, pancreatitis, oesophagitis andbiliary colic.

Similarly, the products of the present invention may be useful in theprevention and/or treatment of respiratory disorders such as asthma,coughing, COPD, bronchoconstriction and inflammatory disorders. Theseproducts may also be used for preventing and/or treating psoriasis,pruritus, dermal, ocular or mucous irritation, herpes and zona.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising a compound according to theinvention as active principle. These pharmaceutical compositions containan effective dose of at least one compound according to the invention,or a pharmaceutically acceptable salt, a hydrate or solvate of the saidcompound, and also at least one pharmaceutically acceptable excipient.

The said excipients are chosen, according to the pharmaceutical form andthe desired mode of administration, from the usual excipients known tothose skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or the possible salt, solvate orhydrate thereof, may be administered in a unit administration form, as amixture with standard pharmaceutical excipients, to man and animals forthe prophylaxis or treatment of the disorders or diseases mentionedabove.

The appropriate unit forms of administration include oral forms such astablets, soft or hard gel capsules, powders, granules and oral solutionsor suspensions, sublingual, buccal, intratracheal, intraocular andintranasal administration forms, forms for administration by inhalation,topical, transdermal, subcutaneous, intramuscular or intravenousadministration forms, rectal administration forms and implants. Fortopical application, the compounds according to the invention may beused in creams, gels, pomades or lotions.

By way of example, a unit form of administration of a compound accordingto the invention in tablet form may comprise the following components:Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodiumcroscaramellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate 3.0 mg

The said unit forms are dosed to allow a daily administration of from0.001 to 30 mg of active principle per kg of body weight, according tothe galenical form.

There may be particular cases in which higher or lower dosages areappropriate: such dosages do not depart from the scope of the invention.According to the usual practice, the dosage that is appropriate for eachpatient is determined by the doctor according to the mode ofadministration, the weight and the response of the said patient.

According to another of its aspects, the present invention also relatesto a method for treating the pathologies indicated above, whichcomprises the administration to a patient of an effective dose of acompound according to the invention, or a pharmaceutically acceptablesalt, or hydrate or solvate thereof.

Although the invention has been illustrated by certain of the precedingexamples, it is not to be construed as being limited thereby; butrather, the invention encompasses the generic area as hereinbeforedisclosed. Various modifications and embodiments can be made withoutdeparting from the spirit and scope thereof.

1. A compound of the formula (I)

wherein n is equal to 0, 1, 2 or 3; X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄ andZ₅ represent, independently of each other, a hydrogen or halogen atom ora C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, cyano, C(O)NR₁R₂,nitro, NR₁R₂, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl,SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅ or aryl group, the aryl being optionallysubstituted with one or more substituents chosen from a halogen and aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy, C₁-C₆-fluoroalkoxy, nitro or cyanogroup; R₁ and R₂ represent, independently of each other, a hydrogen atomor a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene oraryl group; or R₁ and R₂ form, together with the nitrogen atom thatbears them, an azetidine, pyrrolidine, piperidine, azepine, morpholine,thiomorpholine, piperazine or homopiperazine group, said group beingoptionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene or aryl group; R₃ and R₄ represent,independently of each other, a hydrogen atom or a C₁-C₆-alkyl or arylgroup; R₅ represents a C₁-C₆-alkyl or aryl group; W represents a fusedbicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4; A represents a5- to 7-membered heterocycle comprising from one to three heteroatomschosen from O, S and N, wherein if one or more sulfur and/or nitrogenatoms are present, they are optionally in the oxidized form; the carbonatom(s) of A being optionally substituted with one or more groups chosenfrom a hydrogen atom and a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl,aryl-C₁-C₆-alkylene, oxo or thio group; the nitrogen atom(s) of A beingoptionally substituted with R₆ when the nitrogen is adjacent to a carbonatom substituted with an oxo group, or with R₇ in the other cases; R₆represents a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl, aryl-C₁-C₆-alkyleneor aryl group; R₇ represents a hydrogen atom or a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₃-alkylene, C₁-C₆-fluoroalkyl,aryl-C₁-C₆-alkylene, C₁-C₆-alkyl-C(O)—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-(CO)—, C₁-C₆-fluoroalkyl-C(O)—,C₃-C₇-cycloalkyl-C(O)—, aryl-C(O)—, aryl-C₁-C₆-alkylene-C(O)—,C₁-C₆-alkyl-S(O)₂—, C₁-C₆-fluoroalkyl-S(O)₂—, C₃-C₇-cycloalkyl-S(O)₂—,C₃-C₇-cycloalkyl-C₁-C₃-alkylene-S(O)₂—, aryl-S(O)₂— oraryl-C₁-C₆-alkylene-S(O)₂— or aryl group; and W is other than indolyl;or an addition salt thereof, or a hydrate or a solvate thereof.
 2. Thecompound of formula (I) according to claim 1, wherein n is equal to 0 or1; or an addition salt, a hydrate or a solvate thereof.
 3. The compoundof formula (I) according to claim 1, wherein X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃,Z₄ and Z₅ represent, independently of each other, a hydrogen or halogenatom or a C₁-C₆-alkyl, C₁-C₆-fluoroalkyl or C₁-C₆-alkoxy group; or anaddition salt, a hydrate or a solvate thereof.
 4. The compound offormula (I) according to claim 1, wherein W is chosen from indolinyl,isoindolinyl, benzofuryl, dihydrobenzofuryl, benzothiophenyl,dihydrobenzothiophenyl, benzoxazolyl, dihydrobenzoxazolinyl,isobenzofuryl, dihydroisobenzofuryl, benzimidazolyl,dihydrobenzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl,dihydroisobenzothiazolyl, benzotriazolyl, quinolyl, dihydroquinolyl,tetrahydroquinolyl, isoquinolyl, dihydroisoquinolyl,tetrahydroisoquinolyl, benzoxazinyl, dihydrobenzoxazinyl,benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, quinazolinyl,dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl,dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl,dihydrophthalazinyl, tetrahydrophthalazinyl, tetrahydrobenz[b]azepinyl,tetrahydrobenz[c]azepinyl, tetrahydrobenz[d]azepinyl,tetrahydrobenzo[b][1,4]diazepinyl, tetrahydrobenzo[e][1,4]diazepinyl,tetrahydrobenzo[b][1,4]oxazepinyl and tetrahydrobenzo[b][1,4]thiazepinylgroups; and the carbon and/or nitrogen atom(s) of the said group Woptionally being substituted as defined in the general formula (I)according to claim 1; or an addition salt, a hydrate or a solvatethereof.
 5. The compound of formula (I) according to claim 4, wherein Wis chosen from isoquinolyl, dihydroquinolyl, tetrahydroquinolyl,benzoxazinyl, dihydrobenzoxazinyl, benzofuryl, indolinyl, benzoxazolyl,indazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, quinolyl,quinoxalinyl groups; the carbon atom(s) of the said group W beingoptionally substituted with one or more groups chosen from an oxo,C₁-C₆-alkyl or aryl group, as defined in the general formula (I) inrelation with A; and/or the nitrogen atom(s) of the said group W beingoptionally substituted with R₆ when the nitrogen is adjacent to a carbonatom substituted with an oxo group, or with R₇ in the other cases, R₆and R₇ being as defined in the general formula (I) according to claim 1in relation with A, with R₆ representing a hydrogen atom or aC₁-C₆-alkyl group, with R₇ representing a hydrogen atom or a C₁-C₆-alkylor C₁-C₆-alkyl-S(O)₂ group; or an addition salt, a hydrate or a solvatethereof.
 6. A process for preparing a compound of formula (I) accordingto claim 1, comprising: reacting a compound of general formula (IV)

in which X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄, Z₅ and n are as defined in theformula (I) according to claim 1 and B represents a C₁-C₄-alkoxy group,with an amide of the compound of formula (V)

wherein W is as defined in the formula (I) according to claim 1, at thereflux point of a solvent, the amide of the compound of formula (V)being prepared via the prior action of trimethylaluminum on the compoundof formula (V).
 7. A process for preparing a compound of formula (I)according to claim 1, comprising: converting a compound of formula (IV)

wherein X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄, Z₅ and n are as defined in theformula (I) according to claim 1 and B represents a hydroxyl group, intothe acid chloride via the action of thionyl chloride at the reflux pointof a solvent; and reacting the compound of formula (IV) obtained above,wherein X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄, Z₅ and n are as defined in theformula (I) according to claim 1, and B represents a chlorine atom, inthe presence of a base, with the compound of formula (V)

wherein W is as defined in the formula (I) according to claim 1; oralternatively subjecting to a coupling reaction a compound of formula(IV) wherein X₁, X₂, X₃, X₄, Z₁, Z₂, Z₃, Z₄, Z₅ and n are as defined inthe formula (I) according to claim 1 and B represents a hydroxyl group,and a compound of formula (V), wherein W is as defined in the formula(I) according to claim 1, in the presence of a coupling agent and abase, in a solvent.
 8. A pharmaceutical composition comprising acompound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt, a hydrate or a solvate thereof, in combination with atleast one pharmaceutically acceptable excipient.
 9. A pharmaceuticalcomposition comprising a compound of formula (I) according to claim 2,or a pharmaceutically acceptable salt, a hydrate or a solvate thereof,in combination with at least one pharmaceutically acceptable excipient.10. A pharmaceutical composition comprising a compound of formula (I)according to claim 3, or a pharmaceutically acceptable salt, a hydrateor a solvate thereof, in combination with at least one pharmaceuticallyacceptable excipient.
 11. A pharmaceutical composition comprising acompound of formula (I) according to claim 4, or a pharmaceuticallyacceptable salt, a hydrate or a solvate thereof, in combination with atleast one pharmaceutically acceptable excipient.
 12. A pharmaceuticalcomposition comprising a compound of formula (I) according to claim 5,or a pharmaceutically acceptable salt, a hydrate or a solvate thereof,in combination with at least one pharmaceutically acceptable excipient.13. A method of treating a disease in a patient, said disease selectedfrom the group consisting of pain and inflammation, urological disorder,gynecological disorder, gastrointestinal disorder, respiratory disorder,psoriasis, pruritus, dermal, ocular or mucous irritation, herpes andzona, comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I) according to claim
 1. 14.A method of treating a disease in a patient, said disease selected fromthe group consisting of pain and inflammation, urological disorder,gynecological disorder, gastrointestinal disorder, respiratory disorder,psoriasis, pruritus, dermal, ocular or mucous irritation, herpes andzona, comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I) according to claim
 2. 15.A method of treating a disease in a patient, said disease selected fromthe group consisting of pain and inflammation, urological disorder,gynecological disorder, gastrointestinal disorder, respiratory disorder,psoriasis, pruritus, dermal, ocular or mucous irritation, herpes andzona, comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I) according to claim
 3. 16.A method of treating a disease in a patient, said disease selected fromthe group consisting of pain and inflammation, urological disorder,gynecological disorder, gastrointestinal disorder, respiratory disorder,psoriasis, pruritus, dermal, ocular or mucous irritation, herpes andzona, comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I) according to claim
 4. 17.A method of treating a disease in a patient, said disease selected fromthe group consisting of pain and inflammation, urological disorder,gynecological disorder, gastrointestinal disorder, respiratory disorder,psoriasis, pruritus, dermal, ocular or mucous irritation, herpes andzona, comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I) according to claim
 5. 18.The method according to claim 13, wherein the disease is pain andinflammation.
 19. The method according to claim 13, wherein the diseaseis urological disorder.
 20. The method according to claim 13, whereinthe disease is gynecological disorder.
 21. The method according to claim13, wherein the disease is gastrointestinal disorder.
 22. The methodaccording to claim 13, wherein the disease is respiratory disorder. 23.The method according to claim 13, wherein the disease is psoriasis. 24.The method according to claim 13, wherein the disease is pruritus. 25.The method according to claim 13, wherein the disease is dermal, ocularor mucous irritation.
 26. The method according to claim 13, wherein thedisease is herpes.
 27. The method according to claim 13, wherein thedisease is zona.